The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth (original) (raw)
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Italian Journal of Pediatrics, 2020
Background Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction and normal head circumference with consequent relative macrocephaly. Addictional findings are protruding forehead in early life, body asymmetry (of upper and lower limbs) and substantial feeding difficulties. Although several genetic mechanisms that cause the syndrome are known, more than 40% of patients with a SRS-like phenotype remain without an etiological diagnosis. In the last few years, different clinical reports have suggested that mutations or deletions of the HMGA2 gene can be responsible for a SRS-like phenotype in patients with negative results of the common diagnostic tests for this syndrome. Case presentation We present a 3-year-old male patient with clinical diagnosis of Silver-Russell Syndrome (SRS) associated with a de novo heterozygous deletion of the long arm of the chromosome 12 (12q14.3) encompassing the HMGA2 gene. Conclusions Our report ...
European Journal of Medical Genetics, 2009
Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to thrive, short stature, learning disabilities and Buschke-Ollendorff lesions in bone and skin. This report on two additional patients with this microdeletion syndrome emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes. We have previously shown that LEMD3 haploinsufficiency is responsible for the Buschke-Ollendorff lesions and now provide strong evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this disorder. The identification of an intragenic HMGA2 deletion in a boy with proportionate short stature and the cosegregation of this deletion with reduced adult height in the extended family of the boy further underscore the role of HMGA2 in regulating human linear growth.
A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype
Journal of human genetics, 2015
Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and post-natal growth retardation, dysmorphic facial features and body asymmetry. About 50% of the patients carry (epi)genetic alterations involving chromosomes 7 or 11.The high proportion of patients with unidentified molecular etiology suggests the involvement of other genes. Interestingly, SRS patients share clinical features with the 12q14 microdeletion syndrome, characterized by several deletions with a 2.6 Mb region of overlap. Among the genes present in this interval, high mobility AT-hook 2 (HMGA2) appears to be the most likely cause of the growth deficiency, due to its described growth control function. To define the role of HMGA2 in SRS, we looked for 12q14 chromosome imbalances and HMGA2 mutations in a cohort of 45 patients with growth retardation and SRS-like phenotype but no 11p15 (epi)mutations or maternal uniparental disomy of chromosome 7 (matUPD7). We identified a novel 7 bp intr...
European Journal of Medical Genetics, 2011
We report on a 9-month old boy carrying a 21 Mb de novo 13q interstitial deletion. The imbalance was detected by chromosomal analysis and investigated by Fluorescence In Situ Hybridization (FISH) and Comparative Genomic Hybridization (array-CGH) using two different platforms: a BAC microarray with 516 kb resolution (Cytochip) and a 15 kb resolution oligonucleotide microarray (Agilent 244K). The deletion has been estimated to span 21.46 Mb on chromosomal bands 13q22.2e13q32.1. The patient has mild/moderate psychomotor retardation, growth hormone insufficiency, hypertelorism, short neck, micrognathia, hypotonia, dysplastic ears and other dysmorphic features. Further investigation revealed that the abnormality is de novo and causative of the patient's phenotype. The described patient is unique among similar rare cases with different deletion breakpoints. It is the first case of 13q22.2q32.1 deletion where the breakpoints are clearly defined, indicating the importance of detailed clinical description and high-resolution genomic analysis for characterization of rare genetic syndromes.
HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. Objective The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. Design, Setting, Patients Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. Results Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For...
Frontiers in Pediatrics, 2020
We describe the case of a seven-year-old female patient who presented in our service with severe developmental delay, intellectual disability, facial dysmorphism, and femur fracture, observed in the context of very low bone mineral density. Array-based single nucleotide polymorphism (SNP array) analysis identified a 113 kb duplication involving the morbid OMIM genes: ANKRD11 (exon1), RPL13, and PGN genes. ANKRD11 deletions are frequently described in association with KBG syndrome, the duplications being less frequent (one case described before). The exome sequencing was negative for pathogenic variants or of uncertain significance in genes possibly associated with this phenotype. The patient presented subtle signs of KBG syndrome. It is known that the phenotype of KBG syndrome has a wide clinical spectrum, this syndrome being often underdiagnosed due to overlapping features with other conditions, also characterized by multiple congenital anomalies and intellectual disability. The particularity of this case is represented by the very low bone mineral density in a patient with 16q24.3 duplication. ANKRD11 haploinsufficiency is known to be associated with skeletal involvement, such as short stature, or delayed bone age. An effect on bone density has been observed only in experimental studies on mice with induced missense mutations in the ANKRD11 gene. This CNV also involved the duplication of the very conserved RPL13 gene, which could have a role for the skeletal phenotype of this patient, knowing the high level of gene expression in bone tissue and also the association with spondyloepimetaphyseal dysplasia Isidor Toutain type, in case of splicing mutations.